Glycogen Synthase Kinase 3β (GSK3β) is a serine/threonine kinase that regulates many aspects of cell function such as gene expression, apoptosis and metabolism, through phosphorylation of a wide variety of cellular substrates. One of the GSK3β substrates is the Wnt signaling molecule β-catenin. Phosphorylation of β-catenin by GSK3β targets β-catenin for ubiquitination and subsequent degradation. Inhibition of GSK3β activity through phosphorylation is the primary mechanism that regulates this widely expressed active kinase. The protein kinase Akt inhibits GSK3β by phosphorylation at N-terminal serine residues. However, preventing Akt-mediated phosphorylation does not affect the cell survival pathway activated through the GSK3β substrate β-catenin. GSK3β activity is also enhanced by phosphorylation on several tyrosine residues. In some instances GSK3β activity is regulated through its sub-cellular localization. The activity of GSK3β is linked to multiple disorders including neurological disorders, diabetes, and cancer.